{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T19:32:10Z","timestamp":1770233530076,"version":"3.49.0"},"reference-count":65,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01EB025825"],"award-info":[{"award-number":["U01EB025825"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>B-cells are essential components of the immune system that neutralize infectious agents through the generation of antigen-specific antibodies and through the phagocytic functions of na\u00efve and memory B-cells. However, the B-cell response can become compromised by a variety of conditions that alter the overall inflammatory milieu, be that due to substantial, acute insults as seen in sepsis, or due to those that produce low-level, smoldering background inflammation such as diabetes, obesity, or advanced age. This B-cell dysfunction, mediated by the inflammatory cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-\u03b1), increases the susceptibility of late-stage sepsis patients to nosocomial infections and increases the incidence or severity of recurrent infections, such as SARS-CoV-2, in those with chronic conditions. We propose that modeling B-cell dynamics can aid the investigation of their responses to different levels and patterns of systemic inflammation.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>The B-cell Immunity Agent-based Model (BCIABM) was developed by integrating knowledge regarding na\u00efve B-cells, short-lived plasma cells, long-lived plasma cells, memory B-cells, and regulatory B-cells, along with their various differentiation pathways and cytokines\/mediators. The BCIABM was calibrated to reflect physiologic behaviors in response to: 1) mild antigen stimuli expected to result in immune sensitization through the generation of effective immune memory, and 2) severe antigen challenges representing the acute substantial inflammation seen during sepsis, previously documented in studies on B-cell behavior in septic patients. Once calibrated, the BCIABM was used to simulate the B-cell response to repeat antigen stimuli during states of low, chronic background inflammation, implemented as low background levels of IL-6 and TNF-\u03b1 often seen in patients with conditions such as diabetes, obesity, or advanced age. The levels of immune responsiveness were evaluated and validated by comparing to a Veteran\u2019s Administration (VA) patient cohort with COVID-19 infection known to have a higher incidence of such comorbidities.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The BCIABM was successfully able to reproduce the expected appropriate development of immune memory to mild antigen exposure, as well as the immunoparalysis seen in septic patients. Simulation experiments then revealed significantly decreased B-cell responsiveness as levels of background chronic inflammation increased, reproducing the different COVID-19 infection data seen in a VA population.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The BCIABM proved useful in dynamically representing known mechanisms of B-cell function and reproduced immune memory responses across a range of different antigen exposures and inflammatory statuses. These results elucidate previous studies demonstrating a similar negative correlation between the B-cell response and background inflammation by positing an established and conserved mechanism that explains B-cell dysfunction across a wide range of phenotypic presentations.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pcbi.1011776","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T18:24:45Z","timestamp":1706034285000},"page":"e1011776","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Examining B-cell dynamics and responsiveness in different inflammatory milieus using an agent-based model"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2577-9455","authenticated-orcid":true,"given":"Bryan","family":"Shin","sequence":"first","affiliation":[]},{"given":"Gary","family":"An","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-7617","authenticated-orcid":true,"given":"R. 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Frasca","year":"2018","journal-title":"Exp Gerontol"},{"issue":"10","key":"pcbi.1011776.ref012","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: a new immune-metabolic viewpoint for age-related diseases.","volume":"14","author":"C Franceschi","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"pcbi.1011776.ref013","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.exger.2014.01.004","article-title":"High TNF-alpha levels in resting B cells negatively correlate with their response","volume":"54","author":"D Frasca","year":"2014","journal-title":"Exp Gerontol"},{"issue":"8","key":"pcbi.1011776.ref014","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1055\/a-1878-9566","article-title":"Diabetes and COVID-19: Short- and Long-Term Consequences","volume":"54","author":"C Steenblock","year":"2022","journal-title":"Horm Metab Res"},{"issue":"1","key":"pcbi.1011776.ref015","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s12985-023-01983-7","article-title":"Impaired antibody responses were observed in patients with type 2 diabetes mellitus after receiving the inactivated COVID-19 vaccines.","volume":"20","author":"F Xiang","year":"2023","journal-title":"Virology Journal."},{"key":"pcbi.1011776.ref016","first-page":"1582","article-title":"The Effects of Type 2","volume":"11","author":"G Daryabor","year":"2020","journal-title":"Diabetes Mellitus on Organ Metabolism and the Immune System. 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An","year":"2009","journal-title":"Methods Mol Biol"},{"issue":"8","key":"pcbi.1011776.ref019","doi-asserted-by":"crossref","DOI":"10.3390\/v13081620","article-title":"Comparative Computational Modeling of the Bat and Human Immune Response to Viral Infection with the Comparative Biology Immune Agent Based Model.","volume":"13","author":"C Cockrell","year":"2021","journal-title":"Viruses"},{"issue":"21","key":"pcbi.1011776.ref020","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13215314","article-title":"An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma.","volume":"13","author":"KM Storey","year":"2021","journal-title":"Cancers (Basel)."},{"issue":"3","key":"pcbi.1011776.ref021","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.jtbi.2004.06.031","article-title":"Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model","volume":"231","author":"JL Segovia-Juarez","year":"2004","journal-title":"J Theor Biol"},{"issue":"2","key":"pcbi.1011776.ref022","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/0167-5699(92)90135-T","article-title":"A computer model of cellular interactions in the immune system","volume":"13","author":"F Celada","year":"1992","journal-title":"Immunol Today"},{"key":"pcbi.1011776.ref023","doi-asserted-by":"crossref","unstructured":"Stracquadanio G,Umeton R, Costanza J, nnibali V, Mechelli, Pavone M, et al., editors. Large Scale Agent-Based Modeling of the Humoral and Cellular Immune Response2011; Berlin, Heidelberg: Springer Berlin Heidelberg.","DOI":"10.1007\/978-3-642-22371-6_2"},{"key":"pcbi.1011776.ref024","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1142\/S0129183197000424","article-title":"Simulating the Immune Response on a Distributed Parallel Computer.","volume":"8","author":"F. Castiglione MB","year":"1997","journal-title":"International Journal of Modern Physics C"},{"issue":"5","key":"pcbi.1011776.ref025","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0010-4825(01)00011-7","article-title":"Design and implementation of an immune system simulator","volume":"31","author":"M. Bernaschi aFC","year":"2001","journal-title":"Computers in Biology and Medicine"},{"key":"pcbi.1011776.ref026","author":"M. Bernaschi aFC","year":"2004","journal-title":"C-ImmSim: playing with the immune response"},{"key":"pcbi.1011776.ref027","article-title":"How the interval between prime and boost injection affects the immune response in a computational model of the immune system.","author":"F. Castiglione FM","year":"2012","journal-title":"Computational and Mathematical Methods in Medicine"},{"key":"pcbi.1011776.ref028","doi-asserted-by":"crossref","first-page":"646972","DOI":"10.3389\/fimmu.2021.646972","article-title":"From Infection to Immunity: Understanding the Response to SARS-CoV2 Through In-Silico Modeling.","volume":"12","author":"F Castiglione","year":"2021","journal-title":"Front Immunol"},{"issue":"3","key":"pcbi.1011776.ref029","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.immuni.2016.09.001","article-title":"Germinal Center B Cell Dynamics.","volume":"45","author":"L Mesin","year":"2016","journal-title":"Immunity"},{"key":"pcbi.1011776.ref030","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3389\/fimmu.2017.00221","article-title":"Computational Model Reveals Limited Correlation between Germinal Center B-Cell Subclone Abundancy and Affinity: Implications for Repertoire Sequencing.","volume":"8","author":"P Reshetova","year":"2017","journal-title":"Front Immunol."},{"key":"pcbi.1011776.ref031","first-page":"9","article-title":"Quantitative modeling of the effect of antigen dosage on B-cell affinity distributions in maturating germinal centers.","author":"M Molari","year":"2020","journal-title":"Elife"},{"key":"pcbi.1011776.ref032","author":"U. Wilensky","year":"1999","journal-title":"NetLogo"},{"key":"pcbi.1011776.ref033","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.3389\/fimmu.2018.01285","article-title":"Novel Insights on the Regulation of B Cell Functionality by Members of the Tumor Necrosis Factor Superfamily in Jawed Fish.","volume":"9","author":"C Tafalla","year":"2018","journal-title":"Front Immunol"},{"issue":"4","key":"pcbi.1011776.ref034","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.immuni.2015.04.005","article-title":"Regulatory B cells: origin, phenotype, and function","volume":"42","author":"EC Rosser","year":"2015","journal-title":"Immunity"},{"issue":"1","key":"pcbi.1011776.ref035","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.smim.2007.12.001","article-title":"Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function","volume":"20","author":"CD Allen","year":"2008","journal-title":"Semin Immunol"},{"issue":"6","key":"pcbi.1011776.ref036","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.humpath.2012.10.005","volume":"44","author":"SA Rezk","year":"2013","journal-title":"Hum Pathol"},{"issue":"6","key":"pcbi.1011776.ref037","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1093\/intimm\/dxp041","article-title":"IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation","volume":"21","author":"Y Wu","year":"2009","journal-title":"Int Immunol"},{"issue":"5","key":"pcbi.1011776.ref038","doi-asserted-by":"crossref","first-page":"R1001","DOI":"10.1186\/ar1776","article-title":"Differential expression of chemokine receptors on peripheral blood B cells from patients with rheumatoid arthritis and systemic lupus erythematosus","volume":"7","author":"M Henneken","year":"2005","journal-title":"Arthritis Res Ther"},{"issue":"5","key":"pcbi.1011776.ref039","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1084\/jem.20092210","article-title":"S1P1 receptor directs the release of immature B cells from bone marrow into blood","volume":"207","author":"ML Allende","year":"2010","journal-title":"J Exp Med"},{"issue":"2","key":"pcbi.1011776.ref040","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.jaci.2014.01.037","article-title":"Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis","volume":"134","author":"H Sic","year":"2014","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"pcbi.1011776.ref041","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1097\/QAD.0b013e32835bd1f0","article-title":"Decoupling activation and exhaustion of B cells in spontaneous controllers of HIV infection","volume":"27","author":"G Sciaranghella","year":"2013","journal-title":"AIDS"},{"issue":"6","key":"pcbi.1011776.ref042","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.immuni.2020.11.006","article-title":"Germinal Center and Extrafollicular B Cell Responses in Vaccination, Immunity, and Autoimmunity.","volume":"53","author":"RA Elsner","year":"2020","journal-title":"Immunity"},{"issue":"1","key":"pcbi.1011776.ref043","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/imr.12754","article-title":"The continuing story of T-cell independent antibodies","volume":"288","author":"D Allman","year":"2019","journal-title":"Immunol Rev"},{"key":"pcbi.1011776.ref044","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.3389\/fimmu.2019.01787","article-title":"Remembrance of Things Past: Long-Term B Cell Memory After Infection and Vaccination.","volume":"10","author":"AE Palm","year":"2019","journal-title":"Front Immunol"},{"key":"pcbi.1011776.ref045","doi-asserted-by":"crossref","first-page":"965","DOI":"10.3389\/fimmu.2019.00965","article-title":"Survival of Long-Lived Plasma Cells (LLPC): Piecing Together the Puzzle.","volume":"10","author":"SM Lightman","year":"2019","journal-title":"Front Immunol."},{"key":"pcbi.1011776.ref046","article-title":"Memory B cell differentiation from germinal centers","author":"T. Inoue","year":"2023","journal-title":"International Immunology"},{"key":"pcbi.1011776.ref047","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1146\/annurev.iy.12.040194.001001","article-title":"Germinal centers.","volume":"12","author":"IC MacLennan","year":"1994","journal-title":"Annu Rev Immunol"},{"key":"pcbi.1011776.ref048","doi-asserted-by":"crossref","first-page":"721","DOI":"10.3389\/fimmu.2019.00721","article-title":"The Maintenance of Memory Plasma Cells.","volume":"10","author":"L Khodadadi","year":"2019","journal-title":"Front Immunol."},{"key":"pcbi.1011776.ref049","doi-asserted-by":"crossref","first-page":"296","DOI":"10.3389\/fimmu.2015.00296","article-title":"CXCR5, the Defining Marker for Follicular B Helper T (TFH) Cells","volume":"6","author":"B. Moser","year":"2015","journal-title":"Front Immunol"},{"key":"pcbi.1011776.ref050","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/978-1-4939-7095-7_8","article-title":"Cytokine Expression by T Follicular Helper Cells.","volume":"1623","author":"C Jandl","year":"2017","journal-title":"Methods Mol Biol"},{"issue":"2","key":"pcbi.1011776.ref051","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1084\/jem.20070104","article-title":"Interleukin-10 production by effector T cells: Th1 cells show self control","volume":"204","author":"G. Trinchieri","year":"2007","journal-title":"J Exp Med"},{"issue":"6407","key":"pcbi.1011776.ref052","doi-asserted-by":"crossref","DOI":"10.1126\/science.aao2933","article-title":"Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells","volume":"361","author":"D DiToro","year":"2018","journal-title":"Science"},{"issue":"1","key":"pcbi.1011776.ref053","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cyto.2015.05.010","article-title":"T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production","volume":"75","author":"J. Zhu","year":"2015","journal-title":"Cytokine"},{"issue":"4","key":"pcbi.1011776.ref054","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1097\/00000658-199204000-00009","article-title":"Cytokine serum level during severe sepsis in human IL-6 as a marker of severity","volume":"215","author":"P Damas","year":"1992","journal-title":"Ann Surg"},{"issue":"3","key":"pcbi.1011776.ref055","doi-asserted-by":"crossref","first-page":"e1002418","DOI":"10.1371\/journal.pcbi.1002418","article-title":"Living on three time scales: the dynamics of plasma cell and antibody populations illustrated for hepatitis a virus","volume":"8","author":"M Andraud","year":"2012","journal-title":"PLoS Comput Biol"},{"issue":"4","key":"pcbi.1011776.ref056","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1084\/jem.20062104","article-title":"Repression of BCL-6 is required for the formation of human memory B cells in vitro","volume":"204","author":"TC Kuo","year":"2007","journal-title":"J Exp Med"},{"issue":"3","key":"pcbi.1011776.ref057","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1046\/j.1365-2249.1999.01072.x","article-title":"Naive human T cells can be a source of IL-4 during primary immune responses","volume":"118","author":"DM Bullens","year":"1999","journal-title":"Clin Exp Immunol"},{"issue":"6","key":"pcbi.1011776.ref058","first-page":"669","article-title":"Role of cytokines as a double-edged sword in sepsis","volume":"27","author":"H Chaudhry","year":"2013","journal-title":"In Vivo"},{"issue":"1","key":"pcbi.1011776.ref059","doi-asserted-by":"crossref","first-page":"4842","DOI":"10.1038\/s41598-022-08976-6","article-title":"Interferon-gamma signal drives differentiation of T-bet(hi) atypical memory B cells into plasma cells following Plasmodium vivax infection.","volume":"12","author":"P Kochayoo","year":"2022","journal-title":"Sci Rep."},{"issue":"1","key":"pcbi.1011776.ref060","doi-asserted-by":"crossref","first-page":"279","DOI":"10.4049\/jimmunol.1003964","article-title":"A molecular mechanism for TNF-alpha-mediated downregulation of B cell responses","volume":"188","author":"D Frasca","year":"2012","journal-title":"J Immunol"},{"issue":"2","key":"pcbi.1011776.ref061","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1365-2567.2011.03436.x","article-title":"Stromal cells directly mediate the re-establishment of the lymph node compartments after transplantation by CXCR5 or CCL19\/21 signalling","volume":"133","author":"M Buettner","year":"2011","journal-title":"Immunology"},{"issue":"3","key":"pcbi.1011776.ref062","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1681\/ASN.2007091048","article-title":"The role of inflammatory cytokines in diabetic nephropathy","volume":"19","author":"JF Navarro-Gonzalez","year":"2008","journal-title":"J Am Soc Nephrol"},{"issue":"3","key":"pcbi.1011776.ref063","doi-asserted-by":"crossref","first-page":"e0121971","DOI":"10.1371\/journal.pone.0121971","article-title":"Inflammatory cytokines in general and central obesity and modulating effects of physical activity.","volume":"10","author":"FM Schmidt","year":"2015","journal-title":"PLoS One"},{"key":"pcbi.1011776.ref064","doi-asserted-by":"crossref","first-page":"746187","DOI":"10.3389\/fimmu.2021.746187","article-title":"Regulatory B Cells: Role in Type 1 Diabetes.","volume":"12","author":"J Boldison","year":"2021","journal-title":"Front Immunol"},{"issue":"11","key":"pcbi.1011776.ref065","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1038\/s41591-022-02051-3","article-title":"Acute and postacute sequelae associated with SARS-CoV-2 reinfection","volume":"28","author":"B Bowe","year":"2022","journal-title":"Nat Med"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011776","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T18:25:24Z","timestamp":1706034324000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011776"}},"subtitle":[],"editor":[{"given":"James R.","family":"Faeder","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2024,1,23]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011776","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,23]]}}}